Age-related diffuse white matter disease, also known as small vessel disease, is typically associated with white matter hyperintensities (WMHs), a common finding on brain MRI scans (e.g., on FLAIR imaging) in the elderly. Although WMHs have been thought to play a significant role in vascular cognitive impairment and dementia, much remains to be discovered about their pathophysiological cause, cognitive outcome, and progression over time, in particular with in vivo processes. Knowledge of the WMHs is derived predominately from post-mortem studies, which mainly reveal the features of demyelination and axonal degeneration. Due to the limitations and complications of such one-shot and end-stage exams, postmortem studies lack the critical data needed to depict hemodynamic and neural functional pathogenesis. Utilizing an in vivo study will thus be more useful in understanding the pathophysiological characteristics that underpin microcirculation and microstructural changes associated with development and evolution of WMHs. The main objective of this study is to use recently developed multimodal advanced MRI techniques to non-invasively characterize and monitor the vascular pathophysiological changes associated with WMHs over time in the elderly. Such hemodynamic impairment including cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebrovascular reactivity (CVR) underlying WMHs, as well as blood-brain barrier (BBB) water exchange disruption outside WMHs are usually not available on conventional imaging. We hypothesize that the novel quantitative information integrated from this study will help understand relevant microvascular components related to the possible causes of WMHs and their progression over time. Aim 1: Determine hemodynamic profile (i.e., CBF, CBV, and CVR) in the core and penumbra of periventricular and deep WMH as well as NAWM and correlate these vascular measurements with microstructural indices such as fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging (DTI). Aim 2: Examine the associations between the local measures of WMHs (i.e., volume and Fazekas score) and global measures of BBB exchange rate (BBB-x) and neural activity (i.e. cerebral metabolic rate of oxygen or CMRO2) of whole brain (i.e. tissues outside the WMH). Aim 3: Conduct a 30-month (2.5-year) follow-up study of the cohort. We will examine whether increase of WMH burden and worsening of clinical symptoms are accompanied by deterioration of physiological parameters such as BBB-x and CMRO2. We will also determine which vascular parameter(s) can predict the conversion from penumbra or NAWM to WMH over the follow-up period. If successful, this study will provide comprehensive, and newly uncovered, in vivo insights into the microvascular links to formation and progression of WMHs.